Cibor

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CYBOR (ZIBOR)

Composition:

Active substance: bemiparin sodium;

1 ml of injectable solution contains 25,000 IU anti-factor Xa (activity is stated in international units of anti-factor Xa activity according to the 1st International Standard for low-molecular-weight heparin);

1 pre-filled syringe of 0.2 ml contains 5,000 IU anti-factor Xa of bemiparin sodium;

1 pre-filled syringe of 0.3 ml contains 7,500 IU anti-factor Xa of bemiparin sodium;

1 pre-filled syringe of 0.4 ml contains 10,000 IU anti-factor Xa of bemiparin sodium;

Excipient: water for injections.

Pharmaceutical form. Injectable solution.

Main physicochemical properties: clear, particle-free solution ranging in color from colorless to yellow.

Pharmacotherapeutic group. Antithrombotic agents. Heparin group.

ATC code B01AB12.

Pharmacological properties.

Pharmacodynamics.

Bemiparin sodium is a low molecular weight heparin (LMWH) obtained by depolymerization of sodium heparin isolated from porcine intestinal mucosa. The average molecular weight (MW) of bemiparin is approximately 3600 daltons. The proportion of molecular chains with MW less than 2000 daltons is less than 35%. The proportion of molecular chains with MW between 2000 and 6000 daltons ranges from 50 to 75%. The proportion of molecular chains with MW above 6000 daltons is less than 15%. The anti-Xa factor activity of bemiparin ranges from 80 to 120 anti-Xa IU per 1 mg of dry substance, while the anti-IIa factor activity ranges from 5 to 20 anti-IIa IU per 1 mg of dry substance. The ratio of anti-Xa to anti-IIa factor activity is approximately 8:1. Experimental studies in animals have demonstrated the antithrombotic activity and moderate hemorrhagic effect of bemiparin. Use of bemiparin in humans confirms its antithrombotic activity and, when the recommended dosage is followed, causes only a slight prolongation of blood coagulation time tests.

Pharmacokinetics.

The pharmacokinetic properties of bemiparin were studied by measuring anti-Xa factor activity in plasma using an amidolytic method with the 1st International Standard for Low Molecular Weight Heparin (National Institute for Biological Standards and Control, NIBSC).

Absorption and elimination processes follow linear first-order kinetics.

Absorption. Bemiparin sodium is rapidly absorbed after subcutaneous injection, with a bioavailability estimated at 96%. Maximum anti-Xa factor activity following prophylactic doses of 2500 IU and 3500 IU is reached within 2–3 hours after subcutaneous injection, with peak activity levels of approximately 0.34±(0.08) and 0.45±(0.07) IU anti-Xa/mL, respectively. Anti-IIa factor activity is not detected when these doses are administered. Maximum anti-Xa factor activity following doses of 5000 IU, 7500 IU, 10000 IU, and 12500 IU is achieved within 3–4 hours after subcutaneous injection, with peak activity levels of approximately 0.54±(0.06), 1.22±(0.27), 1.42±(0.19), and 2.03±(0.25) IU anti-factor-Xa/mL, respectively. Anti-IIa factor activity of approximately 0.01 IU/mL was detected following administration of doses of 7500 IU, 10000 IU, and 12500 IU.

Elimination. The elimination half-life of bemiparin administered at doses ranging from 2500 IU to 12500 IU is between 5 and 6 hours. Therefore, bemiparin should be administered once daily. Currently, there are no data available regarding the ability of bemiparin to bind to plasma proteins, its metabolism, or its elimination in humans.

Elderly patients.

Pharmacokinetic analysis results from a clinical study involving young healthy volunteers and elderly patients (≥65 years) with normal renal function showed no significant differences in the pharmacokinetic profile of bemiparin.

Renal impairment (see sections "Posology and method of administration" and "Special warnings and precautions for use").

Pharmacokinetic analysis results from a clinical study involving young volunteers, elderly patients, and patients with varying degrees of renal impairment (creatinine clearance < 80 mL/min) demonstrate a relationship between multiple prophylactic dosing (3500 IU/24 h) and single therapeutic dosing (115 IU/kg) of bemiparin and creatinine clearance, as well as most pharmacokinetic parameters of anti-Xa factor activity. Furthermore, it was found that the effect of bemiparin (assessed by the area under the concentration-time curve (AUC) of anti-Xa factor activity) was significantly higher in volunteers with severe renal impairment (creatinine clearance < 30 mL/min) compared to other volunteer groups.

On the other hand, pharmacokinetic modeling was performed to evaluate the profile of bemiparin after administration of ten consecutive daily doses. The average maximum anti-Xa factor activity (Cmax), reproduced after administration of ten prophylactic doses (3500 IU/24 h), ranged from 0.35 to 0.60 IU anti-Xa/mL across all groups; however, in the group of volunteers with severe renal impairment (creatinine clearance <30 mL/min), one patient had a Cmax value of 0.81 IU anti-Xa/mL after the tenth dose. Modeling a dose reduction to 2500 IU/24 h predicted Cmax values below 0.60 IU anti-Xa/mL (mean Cmax = 0.42 IU anti-Xa/mL) for all volunteers with severe renal impairment. Additionally, the predicted mean Cmax after administration of ten therapeutic doses (115 IU/kg/24 h) ranged from 0.89 to 1.22 IU anti-Xa/mL across all groups; in a volunteer from the group with severe renal impairment, the Cmax value was 2.09 IU anti-Xa/mL after the last administration. When modeling a dose adjustment to 75% of the therapeutic dose (86.25 IU/kg/24 h), the predicted Cmax for the aforementioned volunteer was 1.60 IU anti-Xa/mL, while the mean Cmax (0.91 IU anti-Xa/mL) for the group with severe renal impairment remained within the range observed in other groups without dose adjustment.

Preclinical safety data

Preclinical data based on conventional safety pharmacology studies, repeated-dose toxicity, genotoxicity, and reproductive toxicity indicate no special hazard to humans.

Acute toxicity and repeated-dose toxicity studies in animals following bemiparin administration revealed changes primarily consisting of reversible, dose-dependent hemorrhagic lesions at the injection site. These were considered to be the result of excessively high pharmacological activity.

In reproductive toxicity studies of bemiparin conducted in pregnant rats and rabbits between days 6 and 18 of gestation, no lethality was observed. The main clinical signs of reproductive toxicity recorded were subcutaneous hematomas, which may also be attributed to the pharmacological effects of the test substance. No embryotoxic effects related to the drug were observed in fetuses, including external structural abnormalities, skeletal malformations, or internal organ damage.

Clinical Characteristics.

Indications.

Treatment of established deep vein thrombosis, with or without pulmonary embolism, in the acute phase.

Contraindications.

• Hypersensitivity to bemiparin or to any of the excipients.
• Hypersensitivity to heparin or its derivatives, including other low molecular weight heparins, or substances of porcine origin.
• History of confirmed immune-mediated heparin-induced thrombocytopenia (HIT) or suspicion thereof.
• Active bleeding or increased risk of bleeding due to coagulation disorders.
• Severe impairment of liver or pancreatic function.
• Injury or surgical procedures involving the central nervous system, organs of vision, or organs of hearing within the past 2 months.
• Disseminated intravascular coagulation (DIC) syndrome associated with heparin-induced thrombocytopenia.
• Acute bacterial endocarditis and subacute bacterial endocarditis.
• Any organic conditions with high risk of bleeding (e.g., active peptic ulcer, hemorrhagic stroke, cerebral aneurysm, or cerebral neoplasia).
• Regional anesthesia and elective surgery are contraindicated in patients receiving heparin for treatment, rather than for prophylaxis.

Interaction with other medicinal products.

Drug interactions of bemiparin have not been studied, and information in this section is based on data obtained from other low molecular weight heparins.

Concomitant use of bemiparin with the following drugs is not recommended:

Vitamin K antagonists, except during the acute phase of treatment in patients with venous thromboembolic disease.

Other anticoagulants, acetylsalicylic acid, other salicylates and NSAIDs, ticlopidine, clopidogrel and other platelet inhibitors, systemic glucocorticoids, and dextran.

All the above-mentioned drugs enhance the pharmacological effect of bemiparin due to additive effects on coagulation and/or platelet function, thereby increasing the risk of bleeding.

If concomitant use cannot be avoided, careful clinical and laboratory monitoring is required.

Concomitant administration of medicinal products that increase serum potassium concentration should be performed under particularly close medical supervision.

Interaction between heparin and intravenously administered nitroglycerin cannot be excluded with regard to bemiparin (this may lead to reduced efficacy).

Special precautions.

The packaging contains a single dose of the drug. After administration, any unused content of the syringe must be disposed of according to current regulations. Do not use the drug if the protective film of the packaging is opened or damaged. Use only clear, colorless or slightly yellow solution free from particles.

Do not administer by intramuscular injection. Due to the risk of hematoma formation, intramuscular injections of other drugs should be avoided during treatment with bemiparin.

The pharmacokinetics of bemiparin may be altered in patients with severe renal impairment (creatinine clearance <30 mL/min). Regular monitoring of such patients is recommended. A careful individual assessment of bleeding and thrombosis risk should be performed before initiating treatment. Dose adjustment is not considered necessary in mild or moderate renal impairment (creatinine clearance 30–80 mL/min), although caution should be exercised (see sections "Dosage and administration" and "Pharmacokinetics").

Caution should be exercised when prescribing the drug to patients with hepatic or renal impairment, uncontrolled arterial hypertension, history of peptic ulcer of the stomach and duodenum, thrombocytopenia, kidney stones or urolithiasis, vascular abnormalities of the iris or retina, as well as with any other organic disorders associated with increased risk of bleeding, and also when performing spinal or epidural anesthesia or lumbar puncture.

Bemiparin, like other low molecular weight heparin agents, may suppress aldosterone secretion by the adrenal glands, leading to hyperkalemia, particularly in patients with diabetes mellitus, chronic renal impairment, existing metabolic acidosis, elevated plasma potassium levels, or in patients receiving potassium-sparing agents. The risk of hyperkalemia increases proportionally with the duration of therapy, but such hyperkalemia is usually reversible. In high-risk patients, plasma electrolyte levels should be determined before initiating bemiparin and monitored regularly during treatment, especially if therapy duration exceeds 7 days.

Occasionally, at the beginning of heparin therapy, mild transient thrombocytopenia (Type I) (platelet count 100,000/mm³–150,000/mm³) may occur, associated with temporary platelet activation. This condition usually does not lead to complications, so therapy may be continued.

Rarely, severe antibody-mediated thrombocytopenia (Type II) with platelet counts significantly below 100,000/mm³ may develop. This reaction typically occurs between days 5 and 21 of therapy. In patients with a history of heparin-induced thrombocytopenia, this complication may develop more rapidly. Therefore, platelet counts should be monitored before starting bemiparin therapy, on day 1 of treatment, then regularly every 3–4 days, and after completion of treatment. In practice, if a significant decrease in platelet count (30–50%) occurs in the presence of bemiparin, other LMWHs, and/or heparins, and is associated with positive or unknown results of in vitro tests for antiplatelet antibodies, bemiparin therapy must be immediately discontinued and alternative treatment initiated.

As with other heparins, cases of skin necrosis have been observed during bemiparin administration, sometimes preceded by erythema or painful erythematous lesions. In such cases, therapy should be immediately discontinued.

Prophylactic use of heparin in combination with epidural or spinal anesthesia or lumbar puncture may very rarely lead to the development of epidural or spinal hematoma, which may result in prolonged or permanent paralysis. The risk of hematoma is increased with the use of epidural or spinal catheters for anesthesia, concomitant use of drugs affecting blood coagulation (e.g., nonsteroidal anti-inflammatory drugs, platelet aggregation inhibitors, or anticoagulants), and traumatic or repeated puncture.

When determining the time interval between the last prophylactic dose of heparin and insertion or removal of an epidural or spinal catheter, the drug characteristics and patient status must be considered. After catheter removal, the next dose of bemiparin may be administered no sooner than 4 hours later. Administration of the next bemiparin dose should also be delayed until completion of the surgical procedure. If the patient is receiving therapeutic doses of bemiparin sodium (115 IU/kg once daily), a longer waiting period (24 hours) will be required.

When deciding on anticoagulant therapy in the context of epidural or spinal anesthesia, extreme caution is required, and frequent monitoring of the patient for neurological symptoms—such as back pain, sensory and motor disturbances (numbness and weakness of the lower limbs), and bowel or bladder dysfunction—is essential. Medical staff must be able to recognize such symptoms. Patients should immediately inform nurses or physicians if these symptoms occur. In case of suspected epidural or spinal hematoma, immediate diagnosis and therapeutic measures, including spinal decompression, must be initiated.

Use during pregnancy or breastfeeding.

Pregnancy.

Animal studies have not revealed any teratogenic effects of bemiparin. Clinical data on the use of bemiparin in pregnant women are limited; therefore, the drug should be prescribed to pregnant women with caution. Currently, there is no information on the ability of bemiparin to cross the placental barrier.

Breastfeeding period.

Currently, there is insufficient information on whether bemiparin is excreted in breast milk. Therefore, if Cibor must be prescribed to breastfeeding women, breastfeeding should be avoided.

Ability to affect reaction speed when driving or operating machinery.

Cibor does not affect or has negligible effect on the ability to drive or operate machinery.

Method of administration and dosage.

The medicinal product should be used immediately after opening.

Adults.

Treatment of deep vein thrombosis. Subcutaneous administration of Cibor at a dose of 115 IU anti-factor Xa per kg body weight once daily is recommended. The recommended duration of treatment is 7±2 days. The daily dose usually corresponds to the following dosages and volumes of prefilled syringes (depending on body weight): <50 kg – 0.2 ml (5000 IU anti-factor Xa); 50–70 kg – 0.3 ml (7500 IU anti-factor Xa); 70 kg – 0.4 ml (10000 IU anti-factor Xa). For patients with body weight exceeding 100 kg, the dose should be calculated at 115 IU anti-factor Xa per kg body weight per day, taking into account the anti-factor Xa concentration of 25000 IU/ml. In the absence of contraindications, oral anticoagulants should be initiated 3–5 days after starting Cibor, with dosage adjusted so that the International Normalized Ratio (INR) is 2–3 times higher than the control value. Cibor administration may be discontinued once the target INR is achieved.

Oral anticoagulant therapy should be continued for at least 3 months.

Elderly patients.

Dose adjustment is not required provided renal function is normal (see sections “Dosage and administration (Renal impairment)”, “Special precautions”, “Pharmacokinetics”).

Patients with renal impairment.

(See sections “Special precautions”, “Pharmacokinetics”).

No dose adjustment is necessary in mild or moderate renal impairment (creatinine clearance 30–80 ml/min). However, careful monitoring is recommended.

Severe renal impairment (creatinine clearance <30 ml/min) may affect the pharmacokinetics of bemiparin. After careful assessment of the individual risk of bleeding and thrombosis in these patients (especially in the presence of pulmonary embolism), dose adjustment may be required. In such cases, based on pharmacokinetic data, up to 75% of the dose (approximately 85 IU anti-Xa/kg once daily) may be recommended for the treatment of established deep vein thrombosis during the acute phase in patients with severe renal impairment. Careful monitoring is recommended. Measurement of peak anti-Xa levels approximately 4 hours after administration should be considered.

Patients with hepatic impairment.

Insufficient data are available to provide recommendations on dose adjustment of bemiparin in this patient population.

Route of administration. Technique of subcutaneous injection.

Prefilled syringes are ready for immediate use and do not require sterilization prior to injection. When administering Cibor subcutaneously, the injection should be given into the subcutaneous fat layer of the anterolateral abdominal area or posterolateral lumbar region, alternating between right and left sides. The needle should be inserted perpendicularly, not at an angle, to its full depth into a skin fold formed by the thumb and index finger. The skin fold should not be released and should be held throughout the injection. The injection site must not be massaged.

Before injection, do not press the plunger to expel air bubbles in order to avoid loss of medicinal product.

Children.

The safety and efficacy of Cibor in children have not been established; therefore, its use in children is not recommended.

Overdose.

The main manifestation of overdose is bleeding. In the event of bleeding, the decision to discontinue bemiparin therapy should be based on the severity of hemorrhage and the risk of thrombosis. Minor hemorrhages rarely require specific treatment. Significant bleeding may require administration of protamine sulfate. Neutralization of bemiparin by protamine sulfate has been studied in in vitro and in vivo systems to observe reduction in anti-Xa activity and effect on activated partial thromboplastin time (aPTT). Protamine sulfate leads to partial reduction of bemiparin's anti-factor Xa activity within 2 hours after intravenous administration at a dose of 1.4 mg protamine sulfate per 100 IU anti-Xa factor.

Adverse reactions.

The most frequently reported adverse reactions were hematoma and/or ecchymosis at the injection site, observed in approximately 15% of patients treated with Cibor. Long-term use of heparin may lead to the development of osteoporosis.

Adverse reactions are classified by organ systems and frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); and not known (cannot be estimated from the available data).

The frequency of adverse reactions with bemiparin corresponds to the frequency of adverse reactions observed with other low-molecular-weight heparin agents and is presented in the table below:

Reporting of suspected adverse reactions: It is very important to report suspected adverse reactions after the medicinal product has been authorized. This allows continuous monitoring of the benefit-risk balance of the medicinal product.

Shelf life.

2 years. After first opening, the Cibor preparation should be used immediately. Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

Store at a temperature not exceeding 25 °C. Do not freeze. Keep out of the reach and sight of children.

Incompatibilities.

This medicinal product must not be mixed with other medicinal products due to lack of compatibility studies.

Packaging.

Blister covered with a protective film containing 2 pre-filled syringes; each containing 0.2 ml, or 0.3 ml, or 0.4 ml of solution for injection; 1, or 5, or 50 blisters per cardboard box.

Prescription category.

Prescription-only.

Manufacturer.

Rovi Farmaceutica Industrial Services, S.A.

Manufacturer's address.

C/Julian Camarero, 35, Madrid, 28037 Madrid, Spain.

Marketing Authorization Holder.

PROPHARMA International Trading Limited.

Address of the Marketing Authorization Holder.

Level 1, LM Complex, Brewery Street, Zone 3, Central Business District, Birkirkara, CBD3040, Malta.